Tamsulosin HCl ((−)-(R)-5-[2-((2-(o-ethoxyphenoxy)ethyl)amino)propyl]-2-methoxy-benzenesulfonamide hydrochloride), the left-handed optical isomers of the following formula (I), is an active drug of improving or mitigating urinary dysfunction caused by anatomical or mechanical urinary obstruction by bladder neck obstruction, and functional urinary obstruction by the excessive contraction of bladder neck, prostatic stroma and proliferated smooth muscle distributed in the urethra. Its action mechanism is under the control of autonomic sympathetic nerve, and it selectively blocks an alpha 1-a drenergic receptor to inhibit the contraction of bladder neck, prostatic smooth muscle and urinary smooth muscle, thus relaxing the bladder neck, the prostate and the urethra, thereby improving or mitigating urinary dysfunction symptoms. It is currently sold in the form of a capsule formulation that is administered one time a day.

Generally, in order that an administered drug exhibits the greatest effect, the in vivo concentration of the drug needs to be maintained constantly over an extended period of time. For this, control of the release rate of the drug from a formulation containing the drug is necessary, and thus, extensive studies to develop a variety of sustained-release formulations have been conducted in the art.
Of such sustained-release formulations, an oral sustained-release formulation whose drug release is mainly controlled throughout the gastrointestinal tract can increase the patient's compliance with drug treatment, reduce the number of treatments to be administered, and avoid the excessively high concentration of a drug in blood. Accordingly, the oral formulation can not only reduce side effects, but also maintain the drug at optimal therapeutic concentration over an extended period of time, thus increasing a therapeutic effect.
A typical example of such oral sustained-release formulations includes diffusion-type controlled-release formulations, particularly controlled-release capsule formulations having an insoluble coating. In such capsule formulations, the outer surface of a core (tablet or granule) containing a drug is coated with an insoluble coating. As the drug within the capsule is dissolved by digestive fluid infiltrated from the outside, the dissolved drug is diffused and released through the fine pores of the insoluble coating. These capsule formulations are commercially widely used because their preparation is relatively easy.
U.S. Pat. No. 4,772,475 (corresponding to Korean patent publication No. 93-7245; Yamanouchi Pharmaceutical Co., Ltd.) discloses a method for preparing an oral controlled-release pharmaceutical formulation containing tamsulosin HCl as an active ingredient. In order that tamsulosin HCl shows a sustained effect when administered orally, the disclosed method comprises: mixing tamsulosin HCl with a units-forming substance (i.e., crystalline cellulose as an excipient) that is not easily disintegrated in the gastrointestinal tract; adding a release-controlling agent/water mixture to the tamsulosin HCl/crystalline cellulose mixture, the release-controlling agent being selected from the group consisting of acrylic add polymers, acrylic add copolymers and mixtures thereof with cellulose derivatives; granulating the resulting mixture; and forming the granules into individual units (microcapsules or microspheres).
As an oral controlled-release tamsulosin HCl formulation, Harnal® capsule (sold from Yamanouchi Pharmaceutical Co., Ltd.) is prepared by the above prior method comprising: mixing tamsulosin HCl with crystalline cellulose; adding an aqueous emulsion of methacrylic acid copolymer to the mixture; granulating and drying the resulting mixture; spraying and coating and the granules with an aqueous solution of methacrylic acid copolymer; drying and sieving the coated granules. This prior method is being actually applied for the preparation of tamsulosin HCl sustained-release for- mulations. Here, the crystalline cellulose acts as not only an excipient to give a given bulkness, but also a release-controlling agent which helps the sustained release of tamsulosin HCl while maintaining the structure and strength of granules with methacrylic add copolymer, by virtue of its poor water solubility. However, in this prior method, if other general excipients (e.g., lactose and starch) than the crystalline cellulose are used together in the preparation of granules other than a final formulation, the release of tamsulosin HCl will be increased rapidly with the general excipients due to an accelerated increase in water infiltration with time, resulting in a rapid decrease in the physical strength of the granules. This makes the sustained release of tamsulosin HCl difficult.
In addition, in this prior method, since the mixing between a very small amount of tamsulosin HCl and a relatively large amount of crystalline cellulose is first performed, it is difficult to mix them uniformly. Also, to increase the integrity of a formulation, expensive special machines, such as an ultrahigh speed mixer and a fluidized bed granulator for centrifugation, needs to be used. Also, to control the release of a drug uniformly and consistently, only granules having a given size should be screened for the preparation of microcapsules or microspheres, and to provide the granules in the form of tablets or capsules, the addition of additional components is required. Thus, this prior art requires a complicated preparation process and necessarily involves an increase in production cost and a reduction in production yield. Furthermore, if the unit dose of an active ingredient, such as tamsulosin HCl, is low (0.1-0.2 mg/tablet or capsule), drug maldistribution during the mixing of the active ingredient and the excipient (referred to as ‘units-forming substance’) will occur to increase the possibility of occurrence of poor drug content uniformity, thereby increasing the possibility of a failure in maintaining uniform blood drug concentration in vivo.
Meanwhile, as another prior technique that is widely used for the preparation of a pharmaceutical formulation, a method using a solid dispersion may be mentioned. The solid dispersion is generally used according to a melting or solvent process.
In the melting process, a mixture of a poorly soluble drug and a carrier is dissolved by heat and then cooled. However, this process is limited in its applications, since it has problems in that the drug can be modified due to heating, and the properties (e.g., solubility) of the drug can vary depending on cooling rate.
Meanwhile, in the solvent method, a poorly soluble drug and a carrier are dissolved in a solvent capable of solubilizing both the two components, and then dried to remove the solvent. However, if cellulose or other polymers, or copolymers thereof, are used as the carrier, uniform stirring will be difficult due to the high viscosity of the carrier. Also, if the organic solvent is not sufficiently removed, the remaining solvent will affect the physical and chemical stabilities of the solid dispersion. Due to such problems, the solvent method has been considered to be unsuitable for use in industrial mass production.
Accordingly, it has been believed that it is highly difficult to formulate tamsulosin HCl into a tablet showing the satisfactory sustained-release of the drug. For this reason, a tamsulosin HCl sustained tablet has not yet been proposed.